Pheochromocytomas and paragangliomas (PCC/PGL) are tumors of the adrenal medulla or extra-adrenal ganglia, respectively. Most are benign yet still carry high morbidity and mortality due to excessive catecholamine production leading to hypertension, stroke and even death. Approximately one-fourth of PCC/PGLs are malignant, defined by distant metastases. Over one-third of PCC/PGLs have a mutation in one of ten known susceptibility genes, including VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2, NF1, RET, TMEM127 and MAX. Whereas the inherited genetics of this disease and their grouping based on expression profiling and methylation status are well described, somatic mutations and genomic aberrations in PCC/PGL, in particular in relationship to inherited mutations and each other are very poorly understood. The TCGA effort in rare tumors will increase our understanding of the somatic profiles of PCC/PGLs. However, the plans include only 50 tumors, and focus on malignant and/or SDHB mutation positive PCC/PGL, a subset of the known disease spectrum. In Specific Aim 1, we propose a combination of whole exome (in tumor and germline), low coverage (5x) whole genome sequencing (in tumor) and transcriptome sequencing (RNA Seq in tumor) to characterize 30 PCC/PGLs with a lower risk of malignancy, including VHL mutated, and the CIMP-L/0 group, either sporadic (non-SDHx/VHL) or with germline MAPK and PI3K pathway mutations (e.g. RET/NF1), which will complement the TCGA effort. Data analysis will be done across the combined set of 80 TCGA and Penn PCC/PGLs, as we hypothesize that some somatic genetic mutations and genomic aberrations will be common to all PCC/PGLs, despite their differing malignant potential, or occur in sub-sets crossing inherited mutational status. We will validate our findings in 115 independent PCC/PGLs. In Specific Aim 2a, we will determine if distinct patterns of somatic mutations and aberrations are associated with clinically aggressive PCC/PGLs compared to clinically benign PCC/PGLs using 125 samples (80 discoveries, 45 validations). We hypothesize that the pattern of somatic mutations and aberrations will differ in PCC/PGL associated with clinically aggressive disease from clinically benign disease. We will perform an exploratory analysis in Specific Aim 2b to determine if the mutational spectrum differs between PCC/PGLs with different known inherited mutations. These studies will enable us to better understand how mutations in such a broad range of susceptibility genes can lead to the same tumor type, and why the rates of malignant potential vary greatly between inherited mutation groups. We are particularly interested in whether PCC/PGL with different known inherited mutations may have distinct mutational spectra providing insights into the mechanisms promoting tumorigenesis and malignant transformation, which would be relevant for all tumor types. Finally, the results of thi study will allow us to substantially further our understanding of the tumor biology of PCC/PGLs, and identify novel targets for therapeutics for PGL/PCL, which are critically needed.